Monomers derived from hydroxy acids and polymers prepared therefrom

ABSTRACT

A dihydroxy compound characterized by the formula:                    
     Wherein R 1  and R 2  are independently selected from hydrogen and straight and branched alkyl groups containing up to 18 carbon atoms; R 3  is selected from —CH═CH— and (—CH 2 —) k , wherein k is between 0 and 6, inclusive; each Z is independently bromine or iodine, d and n are independently 0, 1 or 2; and X is hydrogen or a pendant group having the structure:                    
     wherein Y is selected from straight and branched alkyl and alkyl and alkylaryl groups containing up to 18 carbon atoms.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional ApplicationSerial Nos. 60/038,213 filed Feb. 18, 1997; 60/064,656 filed Nov. 7,1997; and 60/064,905 filed Nov. 7, 1997. The disclosures of all threeapplications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to monomers prepared from α-, β-, andγ-hydroxy acids and derivatives of the natural amino acid L-tyrosine.The present invention further relates to poly(amide carbonates) andaliphatic-aromatic poly(amide esters) prepared from the monomers of thepresent invention.

BACKGROUND ART

U.S. Pat. No. 5,099,060 discloses diphenolic monomers based on3-(4-hydroxyphenyl) propionic acid and L-tyrosine alkyl esters(desaminotyrosyl-tyrosine alkyl esters). Subsequent related patentsinvolve variations of this basic monomer structure. These monomers,although useful in many applications, have several limitations:

The monomers are insoluble in water and therefore the polymers made fromthem are not readily resorbable. In other words, the previouslydescribed polymers prepared from the previously describedwater-insoluble monomers will not have any weight loss while thedegradation of the polymer backbone results in the loss of mechanicalstrength and reduction in the polymer molecular weight.

The monomers provide two phenolic hydroxyl groups, limiting theresulting polymers to be fully aromatic backbone structures, which maylead to good mechanical strength but slow degradation rate.

Poly(hydroxy acids), such as poly(glycolic acid) (PGA), poly(lacticacid) (PLA) and their copolymers are certainly the most widelyinvestigated synthetic, degradable polymers due to their establishedrecord of safety and FDA approval. Poly(amino acids) derived fromnaturally occurring α-L-amino acids form another major group ofdegradable polymers. Despite their apparent potential as biomaterials,poly(amino acids) have actually found few practical applications. Amajor problem is that most of the poly(amino acids) are highlyintractable (e.g., non-processible, which limits their utility).

Although several copolymers of hydroxy acids and amino acids have beenprepared and evaluated from a biological perspective, theirinvestigation as biomaterials has been rather limited. Helder et al.,J.Biomed. Mater. Res., (24), 1005-1020 (1990) discloses the synthesis ofglycine and DL-lactic acid copolymers and the resulting in vitro and invivo degradation. The elegant synthesis of a copolymer derived fromlactic acid and lysine was reported by Barrera et al., Macromolecules,(28), 425-432 (1995). The lysine residue was utilized to chemicallyattach a cell-adhesion promoting peptide to the copolymer. Otherpolymers of amino acids and hydroxy acids are disclosed by U.S. Pat. No.3,773,737.

The three types of copolymers mentioned above were random copolymersprepared from cyclic monomers by ring-opening polymerization. Thecomposition of the copolymers is highly dependent on the relativereactivity of the two types of cyclic monomers and on the exactpolymerization conditions used. It is hard to control the compositionand hard to predict the polymer properties. Also, there may be largebatch-to-batch variations in the polymer microstructure and sequence.Furthermore, most previous reports described polymers of low molecularweight (M_(w)<10,000) only.

There are only very few degradable polymers for medical uses that havebeen successfully commercialized. Poly(glycolic acid) (PGA), poly(lacticacid) (PLA) and their copolymers are representative examples. Therestill remains a need for biodegradable, especially bioresorbablepolymers suitable for use as tissue-compatible materials. For example,many investigators in the emerging field of tissue engineering haveproposed to engineer new tissues by transplanting isolated cellpopulations on biomaterial scaffolds to create functional new tissues invivo. Bioresorbable materials whose degradation and resorption rates canbe tailored to correspond to the rate of tissue growth are needed. Thiswill require that libraries of many different materials are available sothat the specific polymer properties can be optimally matched with therequirements of the specific application under development.

SUMMARY OF THE INVENTION

This need is met by the present invention. The present inventionprovides a novel class of non-toxic, aliphatic-aromatic dihydroxymonomers and bioresorbable polymers derived therefrom. The monomers areprepared from α-, β-, and γ-hydroxy acids and derivatives of the naturalamino acid L-tyrosine.

Therefore, according to one aspect of the present invention, monomersare provided having a structure according to Formula I:

wherein R₁ and R₂ are each independently selected from H or straight orbranched alkyl groups having up to 18 carbon atoms; R₃ is selected fromthe group consisting of —CH═CH— and (—CH₂—)_(k), wherein k is between 0and 6, inclusive; each Z is an iodine or bromine atom; d and n areindependently 0, 1 or 2; and X is hydrogen or a pendant group having thestructure according to Formula II:

wherein Y is selected from straight or branched alkyl and alkylarylgroups having up to 18 carbon atoms.

In terms of the prior art, the new monomers are similar to thedesaminotyrosyl-tyrosine alkyl esters disclosed in U.S. Pat. No.5,099,060 with the important difference that the desaminotyrosyl unithas been replaced by aliphatic hydroxy acids. In particular, the newdihydroxy monomers are water-soluble. This feature could not have beenpredicted and represents an important difference to the sparinglysoluble desaminotyrosyl-tyrosine alkyl esters disclosed before.

The monomers may be polymerized to form polymers that display excellentphysical, chemical and biological properties, which make them useful asshaped structures such as films, fibers, rods, and in particularpolymeric scaffolds for tissue reconstruction or tissue engineering. Inaddition to being non-toxic in polymer form, the polymers of the presentinvention are expected to form non-toxic degradation products byhydrolytic chain cleavage under physiological conditions. The mostsignificant improvement of the new polymers disclosed here is theirincreased rate of degradation and bioresorption.

The aliphatic-aromatic dihydroxy monomers can be used in the samefashion as the desaminotyrosyl-tyrosine alkyl esters disclosed before.In particular, the monomers can be used to prepare polycarbonates,polyiminocarbonates, polyurethanes, poly(ester amides), and polyethers.Of these many different polymers, aliphatic-aromatic poly(amidecarbonates), and aliphatic-aromatic poly(amide esters) are preferredembodiments.

The present invention therefore also includes aliphatic-aromaticpoly(amide carbonates) prepared from the monomers of the presentinvention. The poly(amide carbonates) are prepared by the processdisclosed by U.S. Pat. No. 5,198,507, the disclosure of which isincorporated herein by reference. The present invention further includesaliphatic-aromatic poly(amide esters) prepared from the monomers of thepresent invention. The poly(amide esters) are prepared by the processdisclosed by U.S. Pat. No. 5,216,115, the disclosure of which is alsoincorporated herein by reference.

Aliphatic-aromatic poly(amide carbonates) according to the presentinvention have the repeating structural units of Formula III:

Aliphatic-aromatic poly(amide esters) according to the present inventionhave the repeating structural units of Formula IV:

In Formulas III and IV, R₁, R₂, R₃, X, Z, d and n are defined exactly asin Formulas I and II. In addition, Y of X may also be hydrogen. R isselected from saturated and unsaturated, substituted and unsubstitutedalkyl, aryl and alkylaryl groups containing up to 24 carbon atoms; and mis the number of repeat units in the average polymer chain and can rangefrom 2 to 1,000.

The poly(amide carbonates) and poly(amide esters) of the presentinvention will degrade faster and will bioresorb faster than prior artpolycarbonates and polyarylates polymerized from desaminotyrosyltyrosinealkyl esters. The polymers of the present invention thus can be used asbiomaterials in all those situations that require a faster degradationand resorption rate than the previously disclosed polymers. Specificapplications for which the polymers of the present invention areparticularly useful include scaffolds for tissue engineering on whichisolated cell populations may be transplanted in order to engineer newtissues and implantable drug delivery devices where a pharmaceuticallyactive moiety is admixed within the polymeric matrix for slow release.

Therefore, the present invention also includes implantable medicaldevices containing the poly(amide carbonates) and poly(ester amides) ofthe present invention. In one embodiment of the present invention, thepolymers are combined with a quantity of a biologically orpharmaceutically active compound sufficient to be therapeuticallyeffective as a site-specific or systemic drug delivery system asdescribed by Gutowska et al., J. Biomater. Res., 29, 811-21 (1995) andHoffman, J. Controlled Release, 6, 297-305 (1987). Furthermore, anotheraspect of the present invention provides a method for site-specific orsystemic drug delivery by implanting in the body of a patient in needthereof an implantable drug delivery device containing a therapeuticallyeffective amount of a biologically or a physiologically active compoundin combination with the poly(amide carbonate) or the poly(ester amide)of the present invention.

In another embodiment of the present invention, the polymers are formedinto porous devices as described by Mikos et al., Biomaterials, 14,323-329 (1993) or Schugens et al., J. Biomed. Mater. Res., 30, 449-462(1996) to allow for the attachment and growth of cells as described inBulletin of the Material Research Society, Special Issue on TissueEngineering (Guest Editor: Joachim Kohn), 21(11), 22-26 (1996).Therefore, another aspect of the present invention provides a tissuescaffold having a porous structure for the attachment and proliferationof cells either in vitro or in vivo formed from the poly(amidecarbonates) and poly(ester amides) of the present invention.

The polymers of the present invention possess excellent physicalproperties and processibility; they can be shaped into differentthree-dimensional structures for specific uses by conventionalpolymer-forming techniques such as solvent casting, extrusion,compression molding, and injection molding.

Other features of the present invention will be pointed out in thefollowing description and claims, which disclose the principles of theinvention in the best modes which are presently contemplated forcarrying them out.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many other intendedadvantages can be readily obtained by reference to the detaileddescription of the invention when considered in connection with thefollowing figures, in which:

FIG. 1 depicts the reduced in vitro degradation of poly(GATE adipate) incomparison to poly(D,L-lactic acid) in PBS (pH=7.4) at 65° C.; and

FIG. 2 depicts the accelerated in vitro degradation of poly(GATEadipate) in comparison to poly(DTE adipate) in PBS (pH=7.4) at 37° C.

BEST MODE OF CARRYING OUT THE INVENTION

Poly(hydroxy acids), such as PGA and PLA, are the most successfulsynthetic biomaterials. However, there are concerns about the acidity oftheir degradation products, their limited range of physicomechanicalproperties, and their simple chemical structure that does not providechemical attachment points for biological ligands, drugs, orcrosslinkers. Thus, attempts have been made to copolymerize hydroxyacids with a wide variety of other components to achieve optimalproperties.

The present invention introduces a novel class of dihydroxy monomers andcopolymers polymerized therefrom in which an α-, β- or γ-hydroxy acid isfirst linked with an L-tyrosine alkyl ester or a structural derivativeof L-tyrosine alkyl esters to form a dihydroxy monomer as defined inFormula I. These new monomers are then polymerized to form strictlyalternating poly(amide carbonates) or they are copolymerized withselected diacids to form poly(amide esters), or they are reacted to formother useful polymers.

The dihydroxy compounds can be used in any conventional polymerizationprocess using diol or diphenol monomers, including those processes thatsynthesize polymers traditionally considered hydrolytically stable andnon-biodegradable.

This includes polyesters, polycarbonates, polyiminocarbonates,polyarylates, polyurethanes, polyethers and random block copolymers ofthe new aliphatic-aromatic dihydroxy monomers with poly(alkylene oxide)as described in U.S. Pat. No. 5,658,995. Particularly preferredembodiments are new poly(amide esters) and new poly(amide carbonates)which will be described in more detail below.

The dihydroxy monomeric starting materials of the present invention havethe structure depicted in Formula I in which R₁, R₂, R₃, X, Z, d and nare the same as described above with respect to Formula I. n ispreferably zero, and R₁ and R₂ are preferably independently selectedfrom hydrogen and methyl. Most preferably, n=0 and at least one of R₁and R₂ is hydrogen, while the other, when not hydrogen, is methyl,resulting in the structures of glycolic acid and the variousstereoisomers of lactic acid, respectively. R₃ is preferably —CH₂—, sothat the dihydroxy monomeric starting material is a derivative ofL-tyrosine. X preferably has a structure according to Formula II inwhich Y is an ethyl, butyl, hexyl, octyl or benzyl group. Y is morepreferably an ethyl group.

When at least one Z is present, polymers prepared from the dihydroxymonomeric starting materials of the present invention are radio-opaque,as disclosed by co-pending and commonly owned U.S. Provisional PatentApplication Serial No. 60/064,905 filed Nov. 7, 1997, the disclosure ofwhich is incorporated herein by reference. The iodinated and brominateddihydroxy monomers of the present invention can also be employed asradio-opacifying, biocompatible non-toxic additives for other polymericbiomaterials.

L-tyrosine is a naturally-occurring amino acid and the hydroxy acid isalso preferably a naturally-occurring, tissue-compatible material. Inthe most preferred embodiments, the dihydroxy monomers of Formula I areprepared by reacting an alkyl or alkylaryl ester of L-tyrosine which mayor may not be iodinated or brominated with a hydroxy acid having thestructure of Formula Ia:

wherein R₁, R₂ and n are the same as described above with respect toFormula I. The L-tyrosine ester is preferably an ethyl, butyl, hexyl,octyl or benzyl ester. The ethyl ester is most preferred.

For the hydroxy acid of Formula Ia, when n is zero and R₁ and R₂ arehydrogen, the hydroxy acid is glycolic acid; and when n is zero, R₁ ishydrogen and R₂ is methyl, and the hydroxy acid is any of thestereoisomers of lactic acid. Glycolic acid is the most preferreddihydroxy compound starting material.

Alkyl and alkylaryl esters of tyrosine containing up to eight carbonatoms are prepared according to the procedure disclosed in J. P.Greenstein and M. Winitz, Chemistry of the Amino Acids, (John Wiley &Sons, New York 1961), p. 927-929. Alkyl and alkylaryl esters of tyrosinecontaining more than eight carbon atoms are prepared according to theprocedure disclosed in Overell, U.S. Pat. No. 4,428,932. Bothdisclosures are incorporated herein by reference. If the tyrosine alkylor alkylaryl esters are initially obtained in their salt form, salts areremoved by a simple washing with aqueous base.

The dihydroxy compounds are then prepared by carbodiimide-mediatedcoupling reactions in the presence of hydroxybenzotriazide according tothe procedure disclosed in U.S. Pat. No. 5,587,507, the disclosure ofwhich is hereby incorporated herein by reference. Suitable carbodiimidesare disclosed therein. The preferred carbodiimide is1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride(EDCI.HCl). A schematic overview of the synthetic route is shown below:

The crude dihydroxy compounds can be recrystallized twice, first from50% acetic acid and water and then from a 20:20:1 ratio of ethylacetate, hexane and methanol. Alternatively, flash chromatography onsilica gel is used, including a 100:2 mixture of methylene chloridemethanol as the mobile phase.

The dihydroxy compounds are then polymerized to form tissue compatiblebioerodible polymers for medical uses. For example, the dihydroxycompounds may be polymerized to form polyiminocarbonates via one of theappropriate methods disclosed by U.S. Pat. No. 4,980,449, the disclosureof which is hereby incorporated herein by reference. According to onemethod, part of the dihydroxy compound is converted to the appropriatedicyanate, then, equimolar quantities of the dihydroxy compound and thedicyanate are polymerized in the presence of a strong base catalyst suchas a metal alkoxide or metal hydroxide. The resulting polyiminocarbonatewill have the structure of Formula VI:

in which R₁, R₂, R₃, X, Z, d and n are the same as described above withrespect to Formula III and m is the number of repeat units in theaverage polymer chain and can range from 2 to 1,000.

The dihydroxy compounds of the present invention may also be reactedwith phosgene to form aliphatic-aromatic poly(amide carbonates) by themethod described by U.S. Pat. No. 5,099,060, the disclosure of which ishereby incorporated by reference thereto. The described method isessentially the conventional method for polymerizing diols intopolycarbonates. Suitable processes, associated catalysts and solventsare known in the art and are taught in Schnell, Chemistry and Physics ofPolycarbonates, (Interscience, New York 1964), the teachings of whichare also incorporated herein by reference. Aliphatic-aromatic poly(amidecarbonates) prepared in accordance with these methods using thedihydroxy compounds of the present invention have repeating structuralunits with the structure of Formula III in which R₁, R₂, R₃, X, Z, d, nand m are the same as described above with respect to Formula III.

The dihydroxy compounds may also be reacted according to the methoddisclosed by U.S. Pat. No. 5,216,115 to form strictly alternatingpoly(amide esters), the disclosure of which is hereby incorporated byreference thereto.

As disclosed by U.S. Pat. No. 5,216,115, the dihydroxy compounds arereacted with aliphatic or aromatic dicarboxylic acids in a carbodiimidemediated direct polyesterification using 4-(dimethylamino)pyridinium-p-toluene sulfonate (DPTS) as a catalyst to form thealiphatic or aromatic poly(ester amides). Dicarboxylic acids suitablefor the polymerization of poly(ester amides) have the structure ofFormula VII:

in which, for the aliphatic poly(ester amides), R is selected fromsaturated and unsaturated, substituted and unsubstituted alkyl groupscontaining up to 18 carbon atoms, and preferably from 2 to 12 carbonatoms that optionally may also include at least one nitrogen or oxygenatom. For the aromatic poly(ester amides), R is selected from aryl andalkylaryl groups containing up to 24 carbon atoms and preferably from 13to 20 carbon atoms that optionally may also include at least onenitrogen or oxygen atom. The resulting poly(amide ester) has thestructure of Formula IV, in which R, R₁, R₂, R₃, X, Z, d, n and m arethe same as described above with respect to Formula IV.

R is preferably selected so that the dicarboxylic acids employed as thestarting materials are either important naturally-occurring metabolitesor highly biocompatible compounds. Preferred aliphatic dicarboxylic acidstarting materials therefore include the intermediate dicarboxylic acidsof the cellular respiration pathway known as the Krebs Cycle. Thesedicarboxylic acids include ac-ketoglutaric acid, succinic acid, fumaricacid and oxaloacetic acid (R of Formula VII is —CH₂—CH₂—C(═O)—,—CH₂—CH₂—, —CH═CCH— and —CH₂C(═O)—, respectively).

Another naturally-occurring, preferred aliphatic dicarboxylic acid isadipic acid (R=(—CH₂—)₄), found in beet juice. Still yet anotherpreferred biocompatible aliphatic dicarboxylic acid is sebacic acid(R=(—CH₂—)₈), which has been studied extensively and has been found tobe nontoxic as part of the clinical evaluation ofpoly(bis(p-carboxyphenoxy)propane-co-sebacic acid anhydride) byLaurencin et al., J. Biomed. Mater. Res., 24, 1463-81 (1990).

Other preferred biocompatible aliphatic dicarboxylic acids includeoxalic acid (no R), malonic acid (R=(—CH₂—)), glutaric acid(R=(—CH₂—)₃), pimelic acid (R=(—CH₂—)₅), suberic acid (R=(—CH₂—)₆) andazelaic acid (R=(—CH₂—)₇). That is, R can represent (—CH—)_(Q), whereinQ is between 0 and 8, inclusive. Among the preferred aromaticdicarboxylic acids are terephthalic acid, isophthalic acid andbis(p-carboxyphenoxy) alkanes such as bis(p-carboxyphenoxy) propane.

The dihydroxy compounds of the present invention may also be useful inthe preparation of polyurethanes where various dihydroxy compounds areused as chain extenders by essentially conventional procedures. Randomor block copolymers of the poly(amide carbonates) and poly(amide esters)of the present invention with a poly(alkylene oxide) may be preparedaccording to the method disclosed in U.S. Pat. No. 5,658,995, thedisclosure of which is also incorporated by reference.

The dihydroxy compounds of the present invention form poly(amidecarbonates) having weight-average molecular weights above about 20,000daltons, and preferably about 80,000 daltons, calculated from gelpermeation chromatography (GPC) relative to polystyrene standards intetrahydrofuran (THF) without further correction. The dihydroxycompounds of the present invention provide poly(ester amides) havingweight average molecular weights above about 20,000 daltons andpreferably above 80,000 daltons, calculated from GPC using THF as theeluent relative to polystyrene standards without further correction.

The polymers of the present invention are defined as including polymershaving pendent free carboxylic acid groups. However, it is not possibleto polymerize polymers having pendent free carboxylic acid groups fromcorresponding monomers with pendent free carboxylic acid groups withoutcross-reaction of the free carboxylic acid group with the co-monomer.Accordingly, polymers in accordance with the present invention havingpendent free carboxylic acid groups are prepared from homopolymers andcopolymers of benzyl ester monomers of the present invention having thestructure of Formula I in which X has the structure of Formula II inwhich Y is a benzyl group.

The benzyl ester homopolymers and copolymers may be converted tocorresponding free carboxylic acid homopolymers and copolymers throughthe selective removal of the benzyl groups by the palladium catalyzedhydrogenolysis method disclosed by co-pending and commonly owned U.S.Provisional Patent Application Serial No. 60/064,656 filed Nov. 7, 1997,the disclosure of which is incorporated herein by reference. Thecatalytic hydrogenolysis is necessary because the lability of thepolymer backbone prevents the employment of harsher hydrolysistechniques.

The polymers of the present invention are also defined as includingradio-opaque bromine- and iodine-substituted polymers. The preparationof such polymers is disclosed in the afore-mentioned co-pending andcommonly owned U.S. Provisional Patent Application Serial No.60/064,905. The disclosure of this application, as it relates to thepolymers of the present invention, is incorporated herein by reference.

The novel monomers of the present invention are especially useful in thepreparation of bioresorbable polymers for biomedical uses. The polymerscan be worked up by known methods commonly employed in the field ofsynthetic polymers to provide a variety of useful articles with valuablephysical and chemical properties. The useful articles can be shaped byconventional polymer-forming techniques such as extrusion, compressionmolding, injection molding, solvent casting, wet spinning, and the like.Shaped articles prepared from the polymers are useful, inter alia asdegradable devices for medical implant applications.

For example, a variety of investigators in the emerging field of tissueengineering have proposed to engineer new tissues by transplantingisolated cell populations on biomaterial scaffolds to create functionalnew tissue in vivo. For this application, relatively fast degradationand fully resorbable polymers are needed. The prior artdesaminotyrosyl-tyrosine alkyl ester degradable polymers are all slowresorbing materials, which do not show any significant weight loss overone year of implantation in vivo. The polymers of the present inventionare designed to address this need.

Additional applications for the polymers disclosed herein include theuse of molded articles such as vascular grafts and stents, bone plates,sutures, implantable sensors, barriers for surgical adhesion prevention,implantable drug delivery devices and other therapeutic aids andarticles which decompose harmlessly within a known period of time. Here,the polymers of the present invention augment the prior artdesaminotyrosyl-tyrosine alkyl ester polymers by providing fasterdegradation and resorption rates. As with the poly(amide carbonates)discussed above, the new poly(amide esters) are also expected to degradefaster and to exhibit faster bioresorption rates than the polyarylatesdisclosed before.

The following non-limiting examples illustrate certain aspects of theinvention. All parts and percentages are by weight, unless otherwisenoted, and all temperatures are in degrees Celsius.

EXAMPLES

The degradation rate (in vitro) and some basic properties of thepolymers of the present invention were evaluated in a comparative studywith poly(D,L-lactic acid) and poly(DTE adipate). Poly(D,L-lactic acid)consists of monomers (lactic acid) that are very water soluble. For manyapplications, poly(D,L-lactic acid) degrades too fast. The use of analiphatic-aromatic dihydroxy monomer with limited water solubility mayreduce the degradation rate of the corresponding polymer. Likewise,compared to the virtually water insoluble monomer of the prior art,desaminotyrosyl-tyrosine alkyl ester, the use of an aliphatic-aromaticdihydroxy monomer with limited water solubility may accelerate thedegradation rate of the corresponding polymer. Thus, polymers derivedfrom the new aliphatic-aromatic dihydroxy monomers may have degradationand resorption rates that are intermediate between that ofpoly(D,L-lactic acid) and those of the desaminotyrosyl-tyrosinepolycarbonates and polyarylates.

To illustrate the utility of this approach, dihydroxy monomer wasprepared from Glycolic Acid and L-Tyrosine Ethyl ester (and therebydesignated as GATE). The GATE was polymerized with either succinic,adipic, suberic, or sebacic acid. This gave rise to a series of fouralternating copolyesters which differed only in the flexibility andhydrophobicity of their polymeric backbone structure: The glasstransition temperature decreased when the number of methylene groups inthe polymer backbone increased. This was expected since the presence ofa larger number of methylene groups increases the flexibility of thepolymer backbone. The air-water contact angle measured at the polymersurface also decreased with an increasing number of methylene groups inthe polymer backbone. This result was unexpected since the contactangle, reflecting the hydrophobicity of the polymer surface, should haveincreased when more methylene groups were added to the polymerstructure.

The in vitro degradation rate of poly(GATE adipate) was compared topoly(D,L-lactic acid) and to the previously disclosed poly(DTE adipate)(wherein DTE refers to desaminotyrosyl-tyrosine ethyl ester) at pH=7.4and at either 65° C. or 37° C., respectively. Since all three polymersare amorphous materials having a similar polyester backbone, the basicdegradation mechanism was expected to be reasonably comparable. The mostsignificant finding was that poly(GATE adipate) degraded slower thanpoly(D,L-lactic acid), but faster than poly(DTE adipate). In addition,unlike poly(D,L-lactic acid), poly(GATE adipate) did not change theenvironmental pH in our study, due to the slower degradation rate andthe significantly smaller amount of acidic degradation products formedper gram of polymer. These findings may translate into a higher degreeof biocompatibility for the new class of polymers.

EXPERIMENTAL

Materials: L-tyrosine, glycolic acid, L-(+)-lactic acid, succinic acid,adipic acid, suberic acid, sebacic acid, thionyl chloride, ethanol,hydroxybenzotriazole hydrate (HOBt), diisopropylcarbodiimide (DIPC),dimethylamino pyridine (DMAP), and p-toluenesulfonic acid were purchasedfrom Aldrich. Ethyl-3-(3-dimethylamino) propyl carbodiimidehydrochloride salt (EDCI.HCl) was obtained from JBL Scientific.Poly(D,L-lactic acid) (M_(w)=1.0×10⁵ dalton) was obtained from MEDISORB.All solvents were HPLC grade and were used as received.

Methods: Nuclear magnetic resonance (NMR) and Fourier transform infrared(FTIR) analysis, were performed on a Varian XL-200-MHz and a MatsonCygnus 100 spectrometer, respectively. Monomer purity and glasstransition temperature (T_(g)) of the polymers were determined by usinga TA Instruments (Model 910) differential scanning calorimeter (DSC).Molecular weights were obtained by gel permeation chromatography (GPC)on a system consisting of a Perkin Elmer pump (Model 410) and a Watersdifferential refractometer (Model 410). Two PL-gel columns (PolymerLaboratories) with pore size 10³ and 10⁵ Å were operated in series at aflow rate of 1 mL/min in THF. Molecular weights were calculated relativeto polystyrene standards. Solvent cast polymer film samples wereprepared for air-water contact angle measurements on a Rame-Hartgontometry (Model 100).

Synthesis: The thionyl chloride technique disclosed in J. P. Greensteinand M. Winitz, Chemistry of the Amino Acids (John Wiley & Sons, New York1961), p. 927-929, was used to prepare L-tyrosine ethyl ester fromL-tyrosine. Glycolic or lactic acid was coupled with L-tyrosine ethylester by using EDCI.HCl as the coupling reagent. The prepared monomers,N-glycolamide-L-tyrosine ethyl ester (GATE) and N-lactamide-L-tyrosineethyl ester (LATE), were then polymerized with phosgene to yieldpoly(amide carbonates) as described by U.S. Pat. No. 5,099,060, or theywere copolymerized with selected diacids (succinic, adipic, suberic andsebacic acids) to form a series of poly(ester amides) using thecarbodiimide mediated direct polymerization technique described in U.S.Pat. No. 5,216,115.

GATE monomer synthesis: Glycolic acid (3.9 g, 0.052 mol), tyrosine ethylester (9.0 g, 0.043 mol), and HOBt (0.174 g, 1.29 mmol) were added in a100 mL round bottom flask equipped with a stirring bar.Dimethylformamide (24 mL) was added. After a short while, a homogenoussolution was obtained. The reaction vessel was cooled in an externalice-water bath and the temperature was maintained at 0-4° C. EDCI.HCl(9.88 g, 0.052 mol) was added and the mixture was stirred for 4 hours,the ice-water bath was removed and the reaction mixture was allowed tostir for an additional 8 hours. To isolate the monomer, 48 mL ethylacetate were added to the flask and stirred for 20 min, followed by theaddition of 20 mL 0.5 M sodium bicarbonate solution. The entire mixturewas transferred into a separatory funnel and the aqueous phase wasremoved. The remaining organic layer, containing most of the product,was washed twice with 20 mL 0.5 M sodium bicarbonate solution and 20 mL20% (w/w) of NaCl. This was followed by three washings with 20 mL eachof 0.4 M HCl and three washings with 20 mL each of 20% (w/w) sodiumchloride solution. After these washings, the organic phase was neutralto pH paper. The organic phase was dried over solid magnesium sulfatepowder, the powder was filtered off and the clear filtrate wasevaporated under reduced pressure. The product was obtained as a lightyellow oil. To this oil, 80 mL hexane was added with stirring. The oilcrystallized into a solid within minutes. The crude solid was collected,washed with 80 mL methylene chloride and dried to constant weight invacuo. 6.8 g GATE was obtained in the form of a white powder, yield 60%,purity 99%. The chemical structure of GATE was confirmed by NMRspectroscopy.

Synthesis of poly(GATE carbonate): All equipment was cleaned and driedin an oven at 120° C. before use. A 250 mL three-neck flask was fittedwith an overhead stirrer. GATE (4.29 g, 0.016 mol) and 36 mL ofmethylene chloride were added. With stirring, pyridine (4.85 mL, 0.064mol) was added and a clear solution was obtained. The reaction mixturewas cooled to about 4° C. with an external ice-water bath. A solution ofphosgene in toluene solution was added (10 mL, 0.019 mol) using a 10 mLsyringe. CAUTION: PHOSGENE IS EXTREMELY TOXIC AND MUST BE USED IN ASUITABLE TOXIC FUME HOOD ONLY. The rate of phosgene addition wascontrolled by a syringe pump and maintained at 3.9 mL/h. After allphosgene had been added, the reaction mixture was stirred for anadditional 90 minutes. During this time, the reaction mixture becameviscous. Thereafter, the reaction mixture was diluted with 40 mL ofmethylene chloride and the precipitated pyridinium hydrochloride wasremoved by filtration. The filtrate containing the majority of theproduct was treated with 800 mL ethyl ether which resulted in theprecipitation of the polymer. The crude polymer was collected byfiltration and purified by dissolution in 40 mL methylene chloride andreprecipitation from 400 mL isopropanol. As a final purification step,the polymer was dissolved in 40 mL tetrahydrofuran and reprecipitated bythe addition of 400 mL of distilled water. Poly(GATE carbonate) (4.3 g)was obtained in the form of a white powder, yield 96%. The weightaverage molecular weight was about 20,000 g/mole.

Synthesis of poly(GATE adipate): Equimolar quantities of GATE and adipicacid were dissolved in methylene chloride, and the polyesterificationwas conducted exactly as described in U.S. Pat. No. 5,216,115 (Example4) for poly(DTE adipate). Typically, poly(GATE adipate) was isolated inabout 50% yield in the form of a white powder with a weight averagemolecular weight of about 100,000 g/mole.

Two separate in vitro degradation studies were carried out to comparethe poly(GATE adipate) degradation rate to the poly(D,L-lactic acid) andpoly(DTE adipate) degradation rates by incubating solvent-cast filmsamples in phosphate buffer solution (pH=7.4) at 37° C. or 65° C. Thebuffer solution was changed weekly and the pH of the buffer solution wasmonitored throughout the degradation process. The molecular weightretention was measured by GPC and each data point is an average of atleast two sample determinations.

RESULTS AND DISCUSSION

The new dihydroxy compounds, GATE and LATE, are the first examples ofmonomers made from aliphatic hydroxy acids and the aminoacid-L-tyrosine. These aliphatic-aromatic dihydroxy monomers were usedto develop new degradable biomaterials. The first four GATE derivedalternating copolyesters were similar in chemical structure, except forthe different number of methylene groups in the polymer backbone (TableI).

TABLE I Chemical Structure of the GATE Derived Alternating Copolyestersm = 2 → Poly(GATE succinate) m = 4 → Poly(GATE adipate) m = 6 →Poly(GATE suberate) m = 8 → PoIy(GATE sebacate)

This small structural variation leads to a large difference in bulk andsurface properties of the polymers (Table II). The glass transitiontemperature (T_(g)) decreased when the number of methylene groups in thepolymer backbone increased. This was expected since the presence of alarger number of methylene groups increases the flexibility of thepolymer backbone. However, the air-water contact angle (θ), measured atthe polymer surface, also decreased with an increasing number ofmethylene groups in the polymer backbone. This result was unexpectedsince the contact angle, reflecting the hydrophobicity of the polymersurface, should have increased when more methylene groups were added tothe polymer structure. Apparently, the composition of the polymersurface is different from that of the polymer bulk, due to thepreferential rearrangement of functional groups (such as the amidebonds) on the polymer surface.

The in vitro degradation rate of poly(GATE adipate) was compared topoly(D,L-lactic acid) in an accelerated degradation study at pH=7.4 and65° C. Since both polymers are amorphous materials having a similarpolyester backbone, the basic degradation mechanism was expected to bereasonably comparable. The most significant finding was the poly(GATEadipate) degraded slower than poly(D,L-lactic acid) (FIG. 1). Inaddition, unlike poly(D,L-lactic acid), poly(GATE adipate) did notchange the environmental pH. It is now generally accepted that theinflammatory reactions of some degradable implant materials correlate tohigh concentration of acidic degradation products. Thus, compared to thewidely used poly(D,L-lactic acid), the new poly(GATE adipate) had aslower degradation rate and released a significantly smaller amount ofacidic degradation products.

The degradation of poly(DTE adipate) and poly(GATE adipate) was comparedat 37° C. to simulate the conditions in the body of a patient. Thisexperiment illustrates the fact that the replacement of the virtuallywater in-soluble and hydrophobic DTE (desaminotyrosyl-tyrosine ethylester) by the more water soluble and hydrophilic GATE within the polymerstructure indeed increased the observed degradation rate of thecorresponding polymers.

Film samples of poly(D)TE adipate) and poly(GATE adipate) were preparedand the molecular weight of incubated samples was determinedperiodically up to 130 days. As shown in FIG. 2, poly(GATE adipate)degraded faster than poly(DTE adipate).

TABLE II Physical Properties of the GATE Derived AlternatingCopolyesters M_(w) M_(n) Polymer (dalton) (dalton) M_(w)/M_(n) T_(g)(°C.) θ (°) Poly(GATE succinate) 54,000 40,000 1.35 58 80 Poly(GATEadipate) 78,000 51,000 1.53 40 79 Poly(GATE suberate) 62,000 41,000 1.5119 72 Poly(GATE sebacate) 90,000 59,000 1.S2 12 70

INDUSTRIAL APPLICABILITY

The new polymers are useful for biomedical applications, including newscaffold materials for tissue engineering and drug release systems.

The foregoing examples and description of the preferred embodimentshould be taken as illustrating, rather than as limiting, the presentinvention as defined by the claims. As will be readily appreciated,numerous variations and combinations of the features set forth above canbe utilized without departing from the present invention as set forth inthe claims. Such variations are not regarded as a departure from thespirit and scope of the invention, and all such modifications areintended to be included within the scope of the following claims.

What is claimed is:
 1. A dihydroxy compound characterized by theformula:

wherein R₁ and R₂ are independently selected from the group consistingof hydrogen and straight and branched alkyl groups containing up to 18carbon atoms; R₃ is selected from the group consisting of —CH═CH— and(—CH₂—)_(k), wherein k is between 0 and 6, inclusive; each Z isindependently bromine or iodine, d and n are independently 0, 1 or 2;and X is hydrogen or a pendant group having the structure:

wherein Y is selected from the group consisting of straight and branchedalkyl and alkylaryl groups containing up to 18 carbon atoms.
 2. Thedihydroxy compound of claim 1, characterized in that n is 0 and R₁ andR₂ are independently selected from the group consisting of hydrogen anda methyl group.
 3. The dihydroxy compound of claim 2, characterized inthat both R₁ and R₂ are hydrogen.
 4. The dihydroxy compound of claim 2,characterized in that one of R₁ or R₂ is hydrogen and the other is amethyl group.
 5. The dihydroxy compound of claim 1, characterized inthat X is said pendent group and Y is selected from the group consistingof ethyl, butyl, hexyl, octyl and benzyl groups.
 6. The dihydroxycompound of claim 5, characterized in that R₃ is —CH₂— and Y is an ethylgroup.
 7. A poly(amide carbonate) characterized by one or more recurringstructural units represented by the formula:

wherein R₁ and R₂ are independently selected from the group consistingof hydrogen and straight and branched alkyl groups containing up to 18carbon atoms; R₃ is selected from the group consisting of —CH═CH— and(—CH₂—)_(k), wherein _(k) is between 0 and 6, inclusive; each Z isindependently bromine or iodine; d and n are independently 0, 1 or 2;and X is hydrogen or a pendent group having the structure:

wherein Y is selected from the group consisting of hydrogen and straightand branched alkyl and alkylaryl groups containing up to 18 carbonatoms.
 8. The poly(amide carbonate) of claim 7, characterized in that nis 0 and R₁ and R₂ are independently selected from the group consistingof hydrogen and a methyl group.
 9. The poly(amide carbonate) of claim 8,characterized in that both R₁ and R₂ are hydrogen.
 10. The poly(amidecarbonate) of claim 8, characterized in that one of R₁ or R₂ is hydrogenand the other is a methyl group.
 11. The poly(amide carbonate) of claim7, characterized in that X is said pendent group and Y is selected fromthe group consisting of ethyl, butyl, hexyl, octyl and benzyl groups.12. The poly(amide carbonate) of claim 11, characterized in that R₃ is—CH₂— and Y is an ethyl group.
 13. A molded article characterized bybeing prepared from the poly(amide carbonate) of claim
 7. 14. Acontrolled drug delivery system characterized by the poly(amidecarbonate) of claim 7, physically admixed with a biologically orpharmacologically active agent.
 15. A controlled drug delivery systemcharacterized by a biologically or pharmacologically active agentphysically embedded or dispersed into a polymeric matrix formed from thepoly(amide carbonate) of claim
 7. 16. A tissue scaffold having a porousstructure for the attachment and proliferation of cells, either in vitroor in vivo, characterized by being formed from the poly(amide carbonate)of claim
 7. 17. A poly(ester amide) characterized by one or morerecurring structural units represented by the formula:

wherein R₁ and R₂ are independently selected from the group consistingof hydrogen and straight and branched alkyl groups containing up to 18carbon atoms; R₃ is selected from the group consisting of —CH═CH— and(—CH₂—)_(k), wherein _(k) is between 0 and 6, inclusive; each Z isindependently bromine or iodine, d and n are independently 0, 1 or 2;and X is hydrogen or a pendent group having the structure:

wherein Y is selected from the group consisting of hydrogen and straightand branched alkyl and alkylaryl groups containing up to 18 carbonatoms; and R is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 24 carbon atoms.
 18. The poly(ester amide) ofclaim 17, characterized in that n is 0 and R₁ and R₂ are independentlyselected from the group consisting of hydrogen and a methyl group. 19.The poly(ester amide) of claim 18, characterized in that both R₁ and R₂are hydrogen.
 20. The poly(ester amide) of claim 18, characterized inthat one of R₁ or R₂ is hydrogen and the other is a methyl group. 21.The poly(ester amide) of claim 17, characterized in that X is saidpendent group and Y is selected from the group consisting of ethyl,butyl, hexyl, octyl and benzyl groups.
 22. The poly(ester amide) ofclaim 21, characterized in that R₃ is —CH₂— and Y is an ethyl group. 23.The poly(ester amide) of claim 17, characterized in that R is selectedfrom the group consisting of saturated and unsaturated, substituted andunsubstituted alkyl groups containing up to 8 carbon atoms.
 24. Thepoly(ester amide) of claim 23, characterized in that R is selected fromthe group consisting of —CH₂—C(═O)—, —CH₂—CH₂—C(═O)—, —CH═CH— and(—CH₂—)_(Q), wherein Q is between 0 and 8, inclusive.
 25. The poly(esteramide) of claim 17, characterized in that R is selected from the groupconsisting of substituted and unsubstituted aryl and alkylaryl groupscontaining from 13 to 20 carbon atoms.
 26. A molded articlecharacterized by being prepared from the poly(ester amide) of claim 17.27. A controlled drug delivery system characterized by the poly(esteramide) of claim 17, physically admixed with a biologically orpharmacologically active agent.
 28. A controlled drug delivery systemcharacterized by a biologically or pharmacologically active agentphysically embedded or dispersed into a polymeric matrix form from thepoly(ester amide) of claim
 17. 29. A tissue scaffold having a porousstructure for the attachment and proliferation of cells, either in vitroor in vivo, characterized by being formed from the poly(ester amide) ofclaim 17.